Given the wide range of clinical presentations for Pompe disease, and the rarity of the disorder, the clinical paths to diagnosis tend to vary tremendously. Infants may present with muscle weakness, feeding difficulty, and/or cardiomegaly while older patients may initially complain of muscle weakness or respiratory distress.

The physical findings in adults may be particularly non-specific and/or suggest more common myopathic disorders. Differential diagnosis is especially difficult due to the wide range of symptoms commonly observed in other diseases and because many Pompe disease symptoms are highly variable across patients. As a result, the diagnosis of Pompe disease may first require the elimination of other possible causes.

While diagnosis is challenging, there are various methods to aid in narrowing down the diagnostic investigation from the clinical manifestations observed. Diagnostic workups, such as electromyography (EMG) or electrocardiography (ECG), may help further reveal the functional manifestation. More targeted tests, such as enzyme level testing, may aid in definitive diagnosis of Pompe disease.

Regardless of what steps precede it, a conclusive diagnosis generally requires that a biopsy of cultured skin fibroblasts or muscle tissue demonstrate reduced or absent activity for the lysosomal enzyme acid alpha-glucosidase (GAA). For those who learn they are at risk of being a Pompe disease carrier during pregnancy, prenatal screening can determine whether an unborn child will be affected by the disease.

At present, no standardized diagnostic protocol has been universally adopted for Pompe disease. Consultation with specialists such as geneticists, neurologists, or endocrinologists who may be more familiar with the disease and who use qualified laboratories may help to expedite the diagnosis.

Enzyme Activity Testing of Cultured Skin Fibroblasts or Muscle Tissue
Enzyme activity testing via a cultured skin fibroblast or muscle biopsy is the definitive step in the diagnostic process, as it can provide proof of low or absent acid alpha-glucosidase (GAA) activity and render a conclusive diagnosis of Pompe disease. Using cultured skin fibroblasts may be preferable to a muscle biopsy due to the less invasive approach. Cultured skin fibroblasts may also be more conclusive in testing for Pompe disease. A muscle biopsy can provide histopathological information about the level of glycogen storage within the lysosomes of muscle cells and may also return faster results.

Enzyme activity testing shows that the GAA deficiency is more pronounced in infantile-onset patients than in late-onset patients. In some infants, the test reveals a complete absence of enzyme activity while in late-onset patients, the severity of the deficiency can vary dramatically. Researchers report that most infants generally demonstrate less than 1% of normal GAA enzyme activity, while juveniles display less than 10% and adults less than 40%, as measured in skin fibroblasts.

Histopathologic examination of muscle biopsies--which is not necessary for a diagnosis but may offer other helpful findings--can reveal the degree of glycogen deposition within the lysosomes of muscle cells. Vacuoles generally stain positive for glycogen and, in some cases, for the lysosomal enzyme acid phosphatase as well. The increase of acid phosphatase, which catalyzes the conversion of orthophosphoric monoester and water into alcohol and orthophosphate, may be due to a compensatory effort. In infantile-onset patients, the increase in glycogen content can be more than tenfold, while the elevation in late-onset patients generally ranges from normal to threefold.

Enzyme Levels (CK, AST, ALT)
A 1999 study found that creatine kinase (CK) elevation is a sensitive marker for Pompe disease. Of 18 patients examined, 18 (100%) demonstrated elevated CK levels, while a review of the literature revealed that 94.3% of patients displayed increased levels. The greatest elevation can be found in infantile-onset patients (as high as 2000 IU/L)[7], while in some cases, adults may have CK levels within the normal reference range. A blood test including a CK examination may be ordered as an early step to determine whether more invasive testing is warranted.

Patients may demonstrate elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). There has been at least one report in which these laboratory findings served as the first clue in a juvenile patient. DiFiore and colleagues in 1993 described a case in which a still asymptomatic juvenile patient presented only with an isolated rise in AST.

Note that Pompe patients typically do not display any abnormalities of glucose metabolism such as hypoglycemia. In addition, Pompe patients usually have normal responses to epinephrine and glucagon administration.

Electromyography (EMG)
In some cases, a neurology consult is requested in the early stages of diagnosis as a result of clinical suspicion of a neuromuscular disorder. An EMG exam generally reveals a myopathic pattern in all Pompe patients, although some muscles may appear normal in late-onset patients. Other common findings may include pseudomyotonic discharges (myotonic discharges without clinical myotonia), fibrillation potentials, positive sharp waves, and excess electrical irritability. In addition, there are usually no abnormalities in conduction times for motor and sensory nerves.

Radiology (X-ray)
In other instances, a chest X-ray showing the presence of cardiomegaly starts the investigation while in other cases another laboratory test provides the first clue.

Echocardiography [ECG] and Electrocardiography (ECHO)
A cardiology consult is generally warranted in infantile-onset patients. Depending on the patient's individualized presentation, this may occur before or after clinical suspicion of a myopathic disorder is aroused.

Both echocardiography and electrocardiography can determine the degree of cardiac involvement. In infants, these imaging studies play a key role in establishing whether the patient has infantile-onset or late-onset Pompe disease. Infantile-onset patients generally show massive cardiomegaly while late-onset patients rarely ever display hypertrophy of the heart.

Certain findings are common in Pompe disease. Echocardiography may reveal left ventricular (LV) thickening and/or outflow obstruction in infantile-onset patients, while the ECG exam typically shows a shortening of the PR interval as well as very tall and broad QRS complexes. Late-onset patients usually have normal patterns.

The clinical manifestations of Pompe disease may present individually or as a suspicious cluster of symptoms, depending on the patient. The following are among the most common signs and symptoms recorded in the literature for the two phenotypes. In the infantile-onset form, the signs and symptoms tend to present swiftly while in the late-onset form, the disease is more slowly progressive. Cognitive function is generally normal in patients with Pompe disease.

Infantile-Onset Form:

• Progressive muscle weakness
• Profound hypotonia
• Macroglossia (and in some cases, protrusion of the tongue)
• Cardiomegaly (massive) and/or cardiac failure
• Respiratory insufficiency
• Failure to meet developmental motor milestones
• Hepatomegaly (moderate)
• Difficulty swallowing, sucking, and/or feeding
• Laxity of facial muscles
• Areflexia

Late-Onset Form:

• Progressive proximal muscle weakness, especially in the trunk
• Progressive muscle weakness in the lower limbs
• Respiratory insufficiency
• Exercise intolerance
• Exertional dyspnea
• Orthopnea
• Sleep apnea
• Morning headaches
• Somnolence
• Lordosis and/or scoliosis
• Hypotonia
• Hepatomegaly
• Macroglossia (uncommon)
• Difficulty chewing or swallowing
• Increased frequency of respiratory infections
• Decreased deep tendon reflexes
• Gower sign
• Lower back pain
• Failure to meet motor milestones (children)

Historically, Pompe disease has sometimes been misdiagnosed as limb girdle muscular dystrophy, Duchenne muscular dystrophy, or polymyositis. Depending on the individual's presenting symptoms and age of onset, there may be several other possible causes to evaluate during the diagnostic query. The table below summarizes the more common differential diagnoses as well as the shared manifestations that may be suggestive of that particular disease.

for Infantile-Onset:

• Acute Werdnig-Hoffman disease (Spinal muscular atrophy I)
• Hypotonia, progressive proximal muscle weakness, absent reflexes
  
  
• Danon disease
• hypertrophic cardiomyopathy, skeletal muscle myopathy, vacuolar storage of glycogen
  
  
• Endocardial fibroelastosis
• Breathlessness, feeding difficulties, cardiomegaly, heart failure
  
  
• Glycogen storage diseases III, VI
• Hypotonia, cardiomegaly, muscle weakness, elevated creatine kinase (CK)
  
  
• Idiopathic hypertrophic cardiomyopathy
• Biventricular hypertrophy
  
  
• Liver failure
• Elevated aspartate aminotransferase (AST), hepatomegaly
  
  
• Mitochondrial disorders
• Hepatomegaly, elevated creatine kinase (CK), cardiomyopathy, myopathy
  
  
• Myocarditis
• Inflammation of the myocardium contributing to cardiac enlargement
  
  

for Late-Onset:

• Duchenne muscular dystrophy (DMD)
• Progressive proximal muscle weakness, respiratory impairment, difficulty walking
  
  
• Glycogen storage diseases III, VI
• Hypotonia, hepatomegaly, muscle weakness, elevated creatine kinase (CK)
  
  
• Glycogen storage disease V
• Elevated creatine kinase (CK), muscle cramps during exercise
  
  
• Liver failure
• Elevated aspartate aminotransferase (AST), hepatomegaly
  
  
• Limb girdle muscular dystrophy (LGMD)
• Progressive muscle weakness in the pelvis, legs, or shoulders
  
  
• Polymyositis
• Unexplained muscle weakness
  
  
• Rigid spine syndrome
• Spinal rigidity, lower back pain
  
  
• Rheumatoid arthritis
• Pain upon exertion
  
  
• Scapuloperoneal syndromes
• Progressive muscle weakness behind the knees and around the shoulder blades
  
  
• Sleep apnea
• Morning headaches, frequent nocturnal awakenings, daytime fatigue and drowsiness

Prenatal diagnosis is available for Pompe disease in cases where it may be warranted, such as subsequent pregnancies in families with an affected child or when a parent presents with the late-onset form. In fact, Pompe disease was one of the first genetic disorders for which researchers attempted diagnosis prior to birth using amniocentesis, with the first published reports appearing in the late 1960s. Today, prenatal diagnosis can be made with either amniocentesis or, more commonly, direct enzyme analysis of uncultured chorionic villi cells, primarily using 4-methylumbelliferyl-a-D-glucoside (4MUG) as substrate. 4MUG is a substance upon which the acid alpha-glucosidase (GAA) enzyme acts

The direct enzyme analysis of uncultured chorionic villi cells offers additional benefits as it allows for early diagnosis (12th week of pregnancy) and potentially as quick as a one day turnaround for results. In some cases, DNA analysis may also be used as a supportive method to confirm a prenatal diagnosis of Pompe disease when the particular defect involved is known. In addition, it can enable definitive carrier detection in the patient's family.

A recent study has explored the use of plasma and dried blood spots to test for Pompe disease in newborns. It remains to be seen how reliable or accepted this diagnostic technique will be in common practice, however.

In the absence of an approved treatment for Pompe disease, supportive therapy is used to manage symptoms and minimize complications whenever possible. While these multidisciplinary approaches cannot generally alter the disease course, they may impact quality of life. Physicians play an important role in coordinating the care for Pompe patients and should be consulted whenever adjunctive care is implemented.

Respiratory Therapy

As a result of the severe weakening of the diaphragm and other respiratory muscles, respiratory therapy may become a critical component of disease management. Many individuals with Pompe disease eventually require mechanical ventilation to reduce or eliminate the work of breathing. Other techniques involve the use of an incentive spirometer and intermittent positive pressure breathing (IPPB) to expand the lungs. Patients requiring 24-hour ventilatory support for prolonged periods may be considered for a tracheostomy.

Dietary Therapy

Dietary therapy is sometimes attempted in Pompe disease as case studies have shown that some patients will demonstrate clinical improvement in conjunction with a high-protein, low-carbohydrate diet or, alternatively, a diet rich in amino acids. In addition, patients who are extremely weak--especially infants--may require tube feeding in order to maintain proper nutrition and prevent aspiration. 

Physical Therapy

Patients who begin to lose mobility due to weakened muscles may also benefit from physical therapy. A customized exercise and/or physical therapy program may help to preserve range of motion and strength, while the use of assistive devices such as orthotics, canes, or walkers may help with ambulation. In advanced cases, a wheelchair may be indicated. 

To devise a full spectrum of supportive therapy, consultation with a respiratory therapist, physical therapist, occupational therapist, speech therapist, and/or registered dietician may be warranted.

RESPIRATORY THERAPY

One of the most crucial avenues of support is respiratory therapy, including the use of mechanical ventilation to aid patients with weakened diaphragms and other respiratory muscles. The use of mechanical ventilation can also prolong survival in late-stage cases, as patients with acute respiratory failure may be able to live for more than a decade longer with proper ventilatory support.

Ideally, patients should be referred to a pulmonologist prior to the onset of respiratory failure, although in many cases the signals may be subtle. Patients with exercise intolerance may not complain of dyspnea given their inability to exert themselves, so other symptoms may present first. Morning headaches and somnolence are two early manifestations that may warrant further investigation. Other signs include a decrease in vital capacity in a supine position and orthopnea. To determine the cause, a sleep evaluation or gas exchange assessment may be indicated.

In many cases, a ventilatory support may only be needed initially at night to address nocturnal carbon dioxide retention and sleep disordered breathing (SDB). Because diurnal hypoventilation usually follows nocturnal hypoventilation, patients may increasingly need ventilation during the day as well.

Non-Invasive Ventilation

Patients with growing respiratory impairment typically begin by using non-invasive ventilation devices that deliver air through a mask that fits over the nose or mouth, or both. These devices provide the advantages of convenience, portability, and low complications. Compared to invasive devices, they are associated with lower cost and morbidity, fewer infections, and reduced caregiver burden.

Currently, there are several different modes of ventilation available depending on patients' needs and ability to breathe spontaneously. Patients with the strength to inhale on their own may prefer a ventilator that follows their own breathing pattern, while others may need a ventilator programmed to automatically deliver breaths in preset cycles. To initiate use, patients are generally referred to a respiratory therapist (RT), who may be available in a hospital or clinic setting. In some cases, the RT may visit patients' homes to provide training and assistance. The RT then typically follows up with patients for several weeks to ensure that the mask fits properly (with no leaks) and adjust the ventilator settings.

Invasive Ventilation

Non-invasive ventilation may not be feasible for small children, patients with claustrophobia, those with excessive secretions, patients with swallowing or coughing difficulty, or advanced cases requiring more intensive respiratory support.

In other cases, patients may not begin mechanical ventilation unless they are hospitalized for respiratory failure, which in some cases occurs when infection potentiates respiratory impairment. Intubation is generally employed in this scenario to deliver conditioned and oxygenated air to the lungs. Once respiratory function stabilizes, "weaning" is usually attempted to determine if patients can breathe on their own entirely, or for a portion of the day. Some patients may not respond to weaning and may become permanently dependent on ventilation, however.

Although definitive guidelines have not been established, patients who appear that they will require mechanical ventilation 24-hours a day for a prolonged period of time and do not respond to weaning may become candidates for tracheostomy. Most modern devices have mechanisms that facilitate speech, such as a one-way valve that can be used along with a deflated cuff to allow patients to converse. Tracheostomy has been associated with improved patient comfort and enhanced ability to participate in rehabilitation-oriented activities.[6] Tracheostomy openings should be cleaned daily to prevent infection.

Another component of respiratory therapy is intermittent positive pressure breathing (IPPB), which can be administered by a RT in the hospital, clinic, or home setting in 10-15 minute sessions. IPPB helps to increase the patient's depth of breathing and can be used to deliver aerosol medications such as mucolytics to the lungs. In some cases, an incentive spirometer may also be employed to increase inhaled lung volume and help eliminate mucus and saliva. Other "respiratory toilet" techniques that may help to clear pulmonary secretions include frequent suctioning and cough assist measures such as chest percussion.

Preventing Infections

Preventing infections is an important part of the total care of Pompe patients. Given that most patients have some degree of respiratory impairment, they are often highly susceptible to pulmonary exacerbations such as bronchitis and pneumonia. Due to this vulnerability, vaccinations such as a flu shot, pneumoccal vaccine, or respiratory syncytial virus (RSV) vaccine may be considered. Infants in particular may encounter aspiration pneumonia as a major complication. As a result, any infection should be treated promptly before it progresses to a more serious stage. Should an infection worsen despite measures to curb it, mechanical ventilation can support patients through this critical period and help to prevent a decline in clinical status.

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